γ-Secretase is the protease responsible for amyloid β peptide release and is needed for Notch, N-Cadherin, and possibly other signaling pathways. The protease complex consists of at least four subunits, i.e., Presenilin, Aph1, Pen2, and Nicastrin. Two different genes encode Aph1A and Aph1B in man. A duplication of Aph1B in rodents has given rise to a third gene, Aph1C . Different mixes of γ-secretase subunits assemble in at least four human and six rodent complexes but it is not known whether they have different activities in vivo . We report here the inactivation of the three Aph1 genes in mice. Aph1A –/– embryos show a lethal phenotype characterized by angiogenesis defects in the yolk sac, neuronal tube malformations, and mild somitogenesis defects. Aph1B –/– or C –/– or the combined Aph1BC –/– mice (which can be considered as a model for total Aph1B loss in human) survive into adulthood. However, Aph1BC –/– deficiency causes a mild but significant reduction in amyloid β percursor protein processing in selective regions of the adult brain. We conclude that the biochemical and physiological repercussions of genetically reducing γ-secretase activity via the different Aph1 components are quite divergent and tissue specific. Our work provides in vivo evidence for the concept that different γ-secretase complexes may exert different biological functions. In the context of Alzheimer's disease therapy, this implies the theoretical possibility that targeting specific γ-secretase subunit combinations could yield less toxic drugs than the currently available general inhibitors of γ-secretase activity.